Download Cancer Prone Disease Section Werner syndrome Atlas of Genetics and Cytogenetics

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Werner syndrome
Mounira Amor-Guéret
Institut Curie - Section de Recherche, UMR 2027 CNRS, Batiment 110, Centre Universitaire, F-91405 Orsay
Cedex, France (MAG)
Published in Atlas Database: October 2000
Online updated version : http://AtlasGeneticsOncology.org/Kprones/WernerID10017.html
DOI: 10.4267/2042/37681
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Cytogenetics
Inheritance
Autosomal recessive; prevalence of carriers is as high
as 1 in 150 to 1 in 200; frequency is about 0.3/105
newborns in Japanese.
Inborn conditions
'Variegated translocation mosaicism': skin fibroblast
cell lines from WRN patients are usually composed of
one or several clones, each marked by a distinctive,
apparently balanced translocation.
Clinics
Other findings
Note
Uncommon disorder characterized by early onset of
geriatric diseases and described as a "caricature of
aging" or "progeria of adults".
Note
WS cells express constitutively high levels of
collagenase in vitro.
WS cells exhibit a mutator phenotype characterized by
extensive deletions: 8-fold higher average frequency of
6-thioguanine-resistant lymphocytes in Werner
syndrome patients than in sex- and age-matched normal
controls.
WS cells usually achieve only about 20 population
doublings versus approximately 60 in normal cells in
culture (WRN gene could be a 'counting' gene
controlling the number of times that human cells are
able to divide before terminal differentiation). Forced
expression of telomerase in Werner syndrome
fibroblasts confers extended cellular life span and
probable immortality.
Phenotype and clinics
Early onset of atherosclerosis, osteoporosis, diabetes
mellitus, scleroderma-like skin changes, especially in
the extremities, cataract, graying of the hair,
subcutaneous calcification, slender limbs, stocky trunk,
beaked nose and cancers of non-epithelial cell origin.
Neoplastic risk
Malignancy is found in approximately 10% of WRN
patients.
Excess of soft-tissue sarcomas, osteosarcomas, myeloid
disorders and benign meningiomas. In addition, the
Japanese have an excess of melanomas and follicular,
and anaplastic thyroid carcinomas.
Genes involved and proteins
Evolution
Complementation groups
No complementation group.
During the first decade of life, WS patients appear
normal: the first manifestation is lack of the adolescent
growth spurt.
In the twenties, WS patients develop bilateral ocular
cataract and premature graying of the hair.
In the thirties and forties, osteoporosis, type II diabete
mellitus, accelerated atherosclerosis, and cancer occur.
In the fourth and fifth decades, WS patients often
succumb to cardiovascular disease or cancer.
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4)
WRN
Location
8p12
Protein
Description: 1432 amino acids; contains one ATP
binding site, one DEXH helicase box, one exonuclease
224
Werner syndrome
Amor-Guéret M
A, Schellenberg GD, Martin GM. Homozygous and compound
heterozygous mutations at the Werner syndrome locus. Hum
Mol Genet. 1996 Dec;5(12):1909-13
domain unique among known RecQ helicases in the Nterminal region, a nuclear localization signal in the Cterminus and a direct repeat of 27 amino acids between
the exonuclease and helicase domains.
Localisation:
Nuclear,
predominant
nucleolar
localization.
Function: 3'-5' DNA helicase; 3'-5' exonuclease;
functionally interacts with DNA polymerase delta
(POLD1), which is required for DNA replication and
DNA repair; functionally interacts with Ku, involved in
double strand DNA break repair by non-homologous
DNA end joining.
Homology: With the RecQ helicases.
Mutations
Germinal: All of the WRN mutations found to date
either create a stop codon or cause frameshifts that lead
to premature termination: not a single missense
mutation had been identified.
Yu CE, Oshima J, Fu YH, Wijsman EM, Hisama F, Alisch R,
Matthews S, Nakura J, Miki T, Ouais S, Martin GM, Mulligan J,
Schellenberg GD. Positional cloning of the Werner's syndrome
gene. Science. 1996 Apr 12;272(5259):258-62
Ogburn CE, Oshima J, Poot M, Chen R, Hunt KE, Gollahon
KA, Rabinovitch PS, Martin GM. An apoptosis-inducing
genotoxin differentiates heterozygotic carriers for Werner
helicase mutations from wild-type and homozygous mutants.
Hum Genet. 1997 Dec;101(2):121-5
Marciniak RA, Lombard DB, Johnson FB, Guarente L.
Nucleolar localization of the Werner syndrome protein in
human cells. Proc Natl Acad Sci U S A. 1998 Jun
9;95(12):6887-92
Ishikawa Y, Sugano H, Matsumoto T, Furuichi Y, Miller RW,
Goto M. Unusual features of thyroid carcinomas in Japanese
patients with Werner syndrome and possible genotypephenotype relations to cell type and race. Cancer. 1999 Mar
15;85(6):1345-52
References
Moser MJ, Oshima J, Monnat RJ Jr. WRN mutations in Werner
syndrome. Hum Mutat. 1999;13(4):271-9
Hoehn H, Bryant EM, Au K, Norwood TH, Boman H, Martin
GM. Variegated translocation mosaicism in human skin
fibroblast cultures. Cytogenet Cell Genet. 1975;15(5):282-98
Cooper MP, Machwe A, Orren DK, Brosh RM, Ramsden D,
Bohr VA. Ku complex interacts with and stimulates the Werner
protein. Genes Dev. 2000 Apr 15;14(8):907-12
Fukuchi K, Martin GM, Monnat RJ Jr. Mutator phenotype of
Werner syndrome is characterized by extensive deletions. Proc
Natl Acad Sci U S A. 1989 Aug;86(15):5893-7
Kamath-Loeb AS, Johansson E, Burgers PM, Loeb LA.
Functional interaction between the Werner Syndrome protein
and DNA polymerase delta. Proc Natl Acad Sci U S A. 2000
Apr 25;97(9):4603-8
Fukuchi K, Tanaka K, Kumahara Y, Marumo K, Pride MB,
Martin GM, Monnat RJ Jr. Increased frequency of 6thioguanine-resistant peripheral blood lymphocytes in Werner
syndrome patients. Hum Genet. 1990 Feb;84(3):249-52
Li B, Comai L. Functional interaction between Ku and the
werner syndrome protein in DNA end processing. J Biol Chem.
2000 Sep 15;275(37):28349-52
Faragher RG, Kill IR, Hunter JA, Pope FM, Tannock C, Shall
S. The gene responsible for Werner syndrome may be a cell
division "counting" gene. Proc Natl Acad Sci U S A. 1993 Dec
15;90(24):12030-4
Wyllie FS, Jones CJ, Skinner JW, Haughton MF, Wallis C,
Wynford-Thomas D, Faragher RG, Kipling D. Telomerase
prevents the accelerated cell ageing of Werner syndrome
fibroblasts. Nat Genet. 2000 Jan;24(1):16-7
Thweatt R, Goldstein S. Werner syndrome and biological
ageing: a molecular genetic hypothesis. Bioessays. 1993
Jun;15(6):421-6
This article should be referenced as such:
Amor-Guéret M. Werner syndrome. Atlas Genet Cytogenet
Oncol Haematol. 2000; 4(4):224-225.
Oshima J, Yu CE, Piussan C, Klein G, Jabkowski J, Balci S,
Miki T, Nakura J, Ogihara T, Ells J, Smith M, Melaragno MI,
Fraccaro M, Scappaticci S, Matthews J, Ouais S, Jarzebowicz
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(4)
225